In vitro-induced human airway hyperresponsiveness to bradykinin

Abstract

Lipopolysaccharide (LPS) and interleukin (IL)-1β have been reported to induce airway hyperresponsiveness in several animal models. This study investigated the effect of LPS or IL-1β on bradykinin-induced human isolated bronchi contraction. LPS (100 ng · mL-1 for 3-6 h) and IL-1β (3x10-10 and 3x10-9 M for 20 min to 3 h) time-dependently potentiated bradykinin- induced contraction. This contraction was abolished, as in control experiments, by indomethacin (10-6 M) or by the thromboxane (Tx) receptor antagonist GR 32191 but not by the cyclo-oxygenase-2 inhibitor, CGP28238. In contrast, the Tx mimetic U46619-induced contraction of human bronchi was not enhanced by IL-1β pretreatment. In the presence of GR 32191 (10-6 M), bradykinin induced a prostanoid dependent relaxation that was not significantly modified by IL-1β pretreatment. Determination of prostanoids in the organ bath fluid showed that bradykinin induced TxB2, the stable metabolite of TxA2, and 6-keto prostaglandin F(1α), the stable metabolite of PGI2, release. Only TxA2 release was potentiated by IL-1β. Taken together our results suggest that interleukin-1β (1-3 h)-induced potentiation of the effect of bradykinin is linked to an increased activity of thromboxane synthase and, in turn, to increased thromboxane synthesis.